It is clear that the progress of toxicological Superfund research during the coming decade will depend upon the mouse as an experimental model to investigate both basic and clinically relevant questions. The high degree of conservation in the genomes of humans and mice makes the approach of using transgene and knock-out gene technology to create models for human toxicology extremely attractive. At the same time, unique differences in metabolism and response to toxic chemicals between mouse and human make the substitution of human genes into the mouse compelling. This core provides this Superfund projects with the most advanced technologies for genetic modification of the mouse genome. Transgenic mice carrying new or novel genes and 'Knock-out' or 'Knock-in' mice lacking specific genes of interest or containing modified version of key genes are created. Conditional expression and Cre/LoxP targeted knock-out strategies are provided. The core provides a wide array of technology- and expertise-intensive services including experimental design consultation, embryonic stem cell homologous recombination, Cre transfection of embryonic stem cells for LoxP excision, blastocyst microinjection of genetically altered embryonic stem cells into blastocysts to create knock-out or knock-in mice, pronuclear injection of transgenes or bacterial artificial chromosomes to create transgenic mice, embryo injecion of Lentivirus vectors, cryopreservation of embryos, and fertility interventions such as in vitro fertilization and ovary transplant. Services are tailored for the projects with special service and high priority. This core is an outstanding example of how extraordinarily specialized techniques, highly trained dedicated personnel, and expensive equipment can be accessed by researchers who could not reasonably expect to develop them on an individual basis. The availability of this Transgenic and Knock-out Mouse Core will enable the projects to conduct versatile, cutting-edge, molecular genetic research in the mouse with a battery of multidisciplinary state-of-the-art techniques.